Molecular control of the leaky vascular barrier in sepsis

Breakdown of the vascular barrier is a critical event for the development of multiple-organ dysfunction and shock. Over the recent years our group explored the Angiopoietin-Tie2 ligand-receptor pathway, a non-redundant pathway controlling endothelial activity, in sepsis and acute kidney injury. The vascular-associated receptor tyrosine kinases Tie2 and its agonist ligand Angiopoietin-1 (Angpt1) were discovered in the mid-1990s. While early studies in Angpt1-/- and Tie2 -/- knockout mice, which die in utero owing to severe vascular defects, revealed the importance of operational Angpt1-Tie2 signaling for developmental angiogenesis, Angpt1 was subsequently identified as a transdominant anti-permeability factor that protects the vasculature of adult mice from plasma leakage induced by vascular endothelial growth factor and other inflammatory stimuli. In contrast, release of Angiopoietin-2 (Angpt-2) from endothelial Weibel-Pallade bodies disrupts the constitutive Angpt1-Tie2 signaling by preventing Angpt1 from binding to the receptor thereby promoting inflammation and permeability. In several studies including our own, plasma Angiopoietin-2 has been shown to predict the severity and mortality in critically ill patients with sepsis and septic shock. We could show that stimulation of the Tie2 receptor, e.g. by pharmacological Tie2-activation, reduces capillary leakage, multiple-organ dysfunction and mortality in various animal models of experimental sepsis and acute kidney injury. A growing number of translational studies have consistently shown that (maintenance of) operational Angpt-1/Tie2 signaling counteracts – and withdrawal of Tie2 phosphorylation by Angpt2 promotes – (hyper-)permeability through multi-level effects on intracellular signaling, cytoskeleton, and junction-related molecules, culminating in the formation of intercellular gaps between endothelial cells. We could recently show that Angpt2 also mediates breakdown of the endothelial glycocalyx, a protective carbohydrate-rich gel-like mesh of large anionic polymers, that lines the luminal side of the endothelium along the entire vascular tree. Mechanistically, Angpt2 causes heparanase secretion from distinctive cellular storage pools with consecutive enzymatic degradation of the glycocalyx. Own in vivo and in vitro experiments using either recombinant Angpt1 or the synthetic Tie2-peptidomimetic Vasculotide strongly suggest that (super)activation of Tie2 may serve as a potential molecular sealant for leaky vessels. 

Tie2 pathways in endothelial cells

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